The object of this proposal is to study the mechanism of benzene toxicity using an interdisciplinary approach involving investigation of the metabolism of benzene, the mechanism by which benzene inhibits cells replication in the regenerating rat liver and the effect of benzene and its metabolites on bone marrow cells in culture. The metabolism studies will concentrate on the disposition of benzene in three strains of mice, i.e., CD1, C57/B6 and DBA/2, which have been shown to display different sensitivities to the bone marrow depressant activity of benzene. The production of benzene metabolites and their localization in the organs of mice will be studied as a function of dose and time of administration. Special attention will be given to studies of the covalent binding of benzene to protein in bone marrow and other organs. The cell replication studies will involve use of isolated rat liver nuclei from partially hepatectomized rats to study effects of benzene on chromosome and DNA replication, effects of benzene on these processes in vivo, study of covalent binding of benzene to DNA and studies of DNA repair in response to benzene induced damage of DNA. The bone marrow cell cultures to be studied are the BFU-E, CFU-E and CFU-C systems. We will evaluate the effects of benzene and its metabolites on the growth of these cultures.